Expression and Regulation of Retinoic Acid Receptor Responders in the Human Placenta

Huebner, Hanna; Hartner, Andrea; Rascher, Wolfgang; Strick, Reiner; Kehl, Sven; Heindl, Felix; Wachter, David; Beckmann, Matthias W.; Fahlbusch, Fabian; Ruebner, Matthias

doi:10.1177/1933719117746761

Cited by 19 publications

(26 citation statements)

References 83 publications

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“…Our previous human studies indicated a dysregulation of the tumor suppressor genes retinoic acid receptor responsive proteins (retinoic acid receptor responders, RARRES) 1 and 2 in the third trimester placentas complicated by preeclampsia (PE) and PE conjoined with intrauterine growth restriction (IUGR) [1,2]. We observed an induction of RARRES1 expression in primary villous cytotrophoblasts isolated from PE and PE/IUGR placentas with a concomitant increase in RARRES1 syncytial staining.…”

Section: Introductionmentioning

confidence: 77%

Expression of Retinoid Acid Receptor-Responsive Genes in Rodent Models of Placental Pathology

Mocker

Schmidt

Huebner

et al. 2019

IJMS

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In humans, retinoic acid receptor responders (RARRES) have been shown to be altered in third trimester placentas complicated by the pathologies preeclampsia (PE) and PE with intrauterine growth restriction (IUGR). Currently, little is known about the role of placental Rarres in rodents. Therefore, we examined the localization and expression of Rarres1 and 2 in placentas obtained from a Wistar rat model of isocaloric maternal protein restriction (E18.5, IUGR-like features) and from an eNOS-knockout mouse model (E15 and E18.5, PE-like features). In both rodent models, Rarres1 and 2 were mainly localized in the placental spongiotrophoblast and giant cells. Their placental expression, as well as the expression of the Rarres2 receptor chemokine-like receptor 1 (CmklR1), was largely unaltered at the examined gestational ages in both animal models. Our results have shown that RARRES1 and 2 may have different expression and roles in human and rodent placentas, thereby underlining immanent limitations of comparative interspecies placentology. Further functional studies are required to elucidate the potential involvement of these proteins in early placentogenesis.

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Section: Introductionmentioning

confidence: 77%

Expression of Retinoid Acid Receptor-Responsive Genes in Rodent Models of Placental Pathology

Mocker

Schmidt

Huebner

et al. 2019

IJMS

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“…Aberrant PIWI proteins, which interact with pi-RNAs to drive post-transcriptional gene regulation, have been found in cancers (Wang et al, 2016), and theoretical evidence from piRNA evolution suggests a role in placentation, although this has yet to be proven empirically (Chirn et al, 2015). In the offspring genome, proteinuria showed an association with placental gene RARB , or retinoic acid (RA) receptor beta (rs4241542, OR 0.26 ± 0.14, p=7.04×10 −6 , MAF 0.21) (Comptour et al, 2016, Huebner et al, 2018), while the strongest association with proteinuria is on a different region, in a SNP intronic to STK32B (rs62297274 (OR 0.35 ± 0.12, p=3.5104×10 −6 ; Supplementary Table 13; Supplementary Figure 32-33). Interestingly, the minor allele for SNP rs62297274 is found at high frequencies in Peruvians compared to other global populations.…”

Section: Resultsmentioning

confidence: 99%

“…RA signaling is essential for healthy placental and fetal development in animal models, with evidence of similar requirement in humans (reviewed in (Comptour, et al, 2016)). RARB is expressed in the extravillous part of the placenta and its activation induces RARRES, shown in one study to be overexpressed in preeclamptic placentas (Huebner, et al, 2018). Our study adds to this body of literature and highlights the role of RA in proper placentation.…”

Section: Discussionmentioning

confidence: 99%

Clotting factor genes are associated with preeclampsia in high altitude pregnant women in the Peruvian Andes

et al. 2021

Preprint

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Study question: What is the genetic basis of preeclampsia in Andean families residing at high altitudes? Summary answer: A top candidate region associated with preeclampsia containing clotting factor genes PROZ, F7 and F10 was found on chromosome 13 of the fetal genome in affected Andean families. What is known already: Preeclampsia, a multi-organ complication of pregnancy, is a leading cause of maternal morbidity and mortality worldwide. Diagnosed by the onset of maternal hypertension and proteinuria after 20 weeks of gestation, this disorder is a common cause of preterm delivery and affects approximately 5-7% of global pregnancies. The heterogeneity of preeclampsia has posed a challenge in understanding its etiology and molecular basis. However, risk for the condition is known to increase in high altitude regions such as the Peruvian Andes. Study design, size, duration: To investigate the genetic basis of preeclampsia in a high-altitude resident population, we characterized genetic diversity in a cohort of Andean families (N=883) from Puno, Peru, a high-altitude city above 3,500 meters. Our study collected DNA samples and medical records from case-control trios and duos between 2011-2016, thus allowing for measurement of maternal, paternal, and fetal genetic factors influencing preeclampsia risk. Participants/materials, setting, methods: We generated high-density genotype data for 439,314 positions across the genome, determined ancestry patterns and mapped associations between genetic variants and preeclampsia phenotype. We also conducted fine mapping of potential causal variants in a subset of family participants and tested ProZ protein levels in post- partum maternal and cord blood plasma by ELISA. Main results and the role of chance: A transmission disequilibrium test (TDT) revealed variants near genes of biological importance in pregnancy physiology for placental and blood vessel function. The most significant SNP in this cluster, rs5960 (p<6x10-6) is a synonymous variant in the clotting factor F10. Two other members of the coagulation cascade, F7 and PROZ, are also in the top associated region. However, we detected no difference of PROZ levels in maternal or umbilical cord plasma. Limitations, reasons for caution: Our genome-wide association analysis (GWAS) was limited by a small sample size and lack of functional follow up. Our ELISA was limited to post-natal blood sampling (only samples collected immediately after birth). But, despite a small sample size, our family based GWAS design permits identification of novel significant and suggestive associations with preeclampsia. Further longitudinal studies could analyze clotting factor levels and activity in other pregnant cohorts in Peru to assess the impact of thrombosis in preeclampsia risk among Andean highlanders. Wider implications of the findings: These findings support previous evidence suggesting that coagulation plays an important role in the pathology of preeclampsia and potentially underlies susceptibility to other pregnancy disorders exacerbated at high altitudes. This discovery of a novel association related to a functional pathway relevant to pregnancy biology in an understudied population of Native American origin demonstrates the increased power of family-based study design and underscores the importance of conducting genetic research in diverse populations.

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“…Previous studies suggested that RARRES1 was involved in the apoptosis of tumor cells, inhibited the proliferation and invasion of tumor cells (42), and placenta formation might share some molecular processes of tumor (43). Studies indicated that RARRES1 was an important regulator of trophoblast cells (44), and its overexpression in trophoblast cells was highly correlated with the onset of preeclampsia (45). There were also reports that RARRES1 in ectopic endometrium of patients with endometriosis was higher than endometrium infertile women of childbearing age, prompting its potential role in endometrial differentiation (46).…”

Section: Discussionmentioning

confidence: 99%

“…the endometrium. As another component of the Notch signaling pathway (45), we speculated that the above changes might be due to the effect of hCG on the Notch signaling pathway in endometrium (49). GC has a strong immunomodulatory and antiinflammatory effect, and is used to treat autoimmune diseases and some malignant lymphomas (52).…”

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confidence: 99%

Transcriptomic changes and potential regulatory mechanism of intrauterine human chorionic gonadotropin co-cultured with peripheral blood mononuclear cells infusion in mice with embryonic implantation dysfunction

Chen¹,

Zhao²,

Ao³

et al. 2020

Ann Transl Med

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Background: This study aimed to explore whether intrauterine infusion of peripheral blood mononuclear cells (PBMCs) could induce favorable transcriptomic changes in the endometrium for embryo implantation and the potential mechanism.Methods: Twenty-one mice were randomly divided to five groups, including a normal pregnancy (NP) group, an embryo implantation dysfunction (EID) group, an EID with human chorionic gonadotropin (hCG) group, an EID with PBMCs group, and an EID with hCG co-cultured with PBMCs group. The endometrium in the implantation window from mice were collected and determined by RNA sequencing (RNA-Seq), and the expression of significantly different genes with high degree of coincidence was recommended and validated by quantitative real-time polymerase chain reaction (qRT-PCR).Results: There were totally 1,366 up-regulated and 1,374 down-regulated genes in the EID mice compared with the normal pregnant mice. We selected (fold change ≥2, P<0.05) and verified the candidate genes associated with embryo implantation, immune response and other reproductive processes in previous reports by qRT-PCR. Leukemia inhibitory factor (LIF), solute carrier family 15 member 2 (SLC15A2), retinoic acid receptor responder 1 (RARRES1), vascular cell adhesion molecule 1 (VCAM1) were down-regulated and musculin (MSC), chemokine (C-X-C motif) ligand 14 (CXCL14) were up-regulated significantly in EID group (P<0.05), and the synergistic effects of hCG were seen. In addition, the expression of glucocorticoid receptor (GR)-β in PBMCs of NP mice was higher than that of EID mice, and up-regulated GR-β in EID mice could significantly increase the expression of LIF, SLC15A2, RARRES1 and VCAM1, and decrease the expression of CXCL14 and MSC, which indicated GR-β might be a transcriptional factor of the six genes above.Conclusions: Intrauterine PBMCs perfusion might improve the performance of impaired endometrial receptivity by regulating LIF, SLC15A2, RARRES1, VCAM1, MSC as well as CXCL14, and hCG could enhance the effect of PBMCs. In addition, GR-β, as a transcriptional factor, could regulate the six genes in PBMCs.

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Expression and Regulation of Retinoic Acid Receptor Responders in the Human Placenta

Cited by 19 publications

References 83 publications

Expression of Retinoid Acid Receptor-Responsive Genes in Rodent Models of Placental Pathology

Expression of Retinoid Acid Receptor-Responsive Genes in Rodent Models of Placental Pathology

Clotting factor genes are associated with preeclampsia in high altitude pregnant women in the Peruvian Andes

Transcriptomic changes and potential regulatory mechanism of intrauterine human chorionic gonadotropin co-cultured with peripheral blood mononuclear cells infusion in mice with embryonic implantation dysfunction

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